INTACT Trial - an Observational Study to Assess Neuropathy in Diabetic Children

NCT05247840 | Not Yet Recruiting DMC

• 1 other identifier: KUT-37/2021
• Study Type: observational
• Target: 350
• Locations: 1 country
• Sites: 1

Brief Summary

It is a prospective, cross-sectional, observational, controlled, single centre clinical study. Diabetic patients fulfilling the inclusion criteria and healthy controls will have uroflowmetry examination, cardiovascular autonomic dysfunction tests (heart rate response to deep breathing, to Valsalva maneuver, blood pressure and heart rate response to standing up, and to sustained handgrip), and peripheral nerve conduction test. The primary endpoint is the diagnostic accuracy (sensitivity, specificity, negative and positive predictive values) of the tests. The secondary endpoints are: differences in metabolic status (weight, height, body surface, BMI, laboratory parameters, body composition), fluid turnover, and clinical symptoms of diabetic patients comparing to healthy children.

Conditions

Diabetes Mellitus

Keywords

diabetes; uroflowmetry; neuropathy; paediatric; children

Outcome Measures

Primary Outcomes (18)

• diagnostic accuracy of uroflowmetry test 1.1

  sensitivity, specificity, positive predictive value, negative predictive value

  baseline

• diagnostic accuracy of uroflowmetry test 1.2

  sensitivity, specificity, positive predictive value, negative predictive value

  change from baseline at 12 months

• diagnostic accuracy of uroflowmetry test 1.3

  sensitivity, specificity, positive predictive value, negative predictive value

  change from baseline at 24 months

• diagnostic accuracy of uroflowmetry test 1.4

  sensitivity, specificity, positive predictive value, negative predictive value

  change from baseline at 36 months

• diagnostic accuracy of uroflowmetry test 1.5

  sensitivity, specificity, positive predictive value, negative predictive value

  change from baseline at 48 months

• diagnostic accuracy of uroflowmetry test 1.6

  sensitivity, specificity, positive predictive value, negative predictive value

  change from baseline at 60 months

• diagnostic accuracy of cardiovascular autonomic dysfunction test 2.1

  sensitivity, specificity, positive predictive value, negative predictive value

  baseline

• diagnostic accuracy of cardiovascular autonomic dysfunction test 2.2

  sensitivity, specificity, positive predictive value, negative predictive value

  change from baseline at 12 months

• diagnostic accuracy of cardiovascular autonomic dysfunction test 2.3

  sensitivity, specificity, positive predictive value, negative predictive value

  change from baseline at 24 months

• diagnostic accuracy of cardiovascular autonomic dysfunction test 2.4

  sensitivity, specificity, positive predictive value, negative predictive value

  change from baseline at 36 months

• diagnostic accuracy of cardiovascular autonomic dysfunction test 2.5

  sensitivity, specificity, positive predictive value, negative predictive value

  change from baseline at 48 months

• diagnostic accuracy of cardiovascular autonomic dysfunction test 2.6

  sensitivity, specificity, positive predictive value, negative predictive value

  change from baseline at 60 months

• diagnostic accuracy of peripheral nerve conduction test 3.1

  sensitivity, specificity, positive predictive value, negative predictive value

  baseline

• diagnostic accuracy of peripheral nerve conduction test 3.2

  sensitivity, specificity, positive predictive value, negative predictive value

  change from baseline at 12 months

• diagnostic accuracy of peripheral nerve conduction test 3.3

  sensitivity, specificity, positive predictive value, negative predictive value

  change from baseline at 24 months

• diagnostic accuracy of peripheral nerve conduction test 3.4

  sensitivity, specificity, positive predictive value, negative predictive value

  change from baseline at 36 months

• diagnostic accuracy of peripheral nerve conduction test 3.5

  sensitivity, specificity, positive predictive value, negative predictive value

  change from baseline at 48 months

• diagnostic accuracy of peripheral nerve conduction test 3.6

  sensitivity, specificity, positive predictive value, negative predictive value

  change from baseline at 60 months

Secondary Outcomes (48)

• metabolic status 1.1

  baseline

• metabolic status 1.2

  change from baseline at 12 months

• metabolic status 1.3

  change from baseline at 24 months

• metabolic status 1.4

  change from baseline at 36 months

• metabolic status 1.5

  change from baseline at 48 months

Study Arms (2)

diabetic children

Children aged 5-18 years (boys, girls) with type 1, type 2 and monogenic diabetes mellitus who are treated at the Endocrinology Department and Outpatient Clinic of Heim Pál National Pediatric Institute (HOGYI, Budapest, Hungary) will be enrolled. Definition of diabetes is based on the American Diabetes Association (ADA) criteria. All patients who meet the inclusion criteria will be informed of the possibility of taking part in the INTACT Trial.

Diagnostic Test: uroflowmetry; Diagnostic Test: Cardiovascular autonomic dysfunction test proposed by Ewing et al.; Diagnostic Test: peripheral nerve conduction test

healthy children

Healthy children aged 5-18 years (boys, girls) without any acute or chronical disease will be will enrolled and the same tests will be performed on them as in diabetic children. Children with voided volume \<20 mL, postvoid residual volume \>15%, and signs of an overstretched bladder \[voided volume more than: 30 x age (years) + 30 mL\] will be excluded.

Diagnostic Test: uroflowmetry; Diagnostic Test: Cardiovascular autonomic dysfunction test proposed by Ewing et al.; Diagnostic Test: peripheral nerve conduction test

Interventions

uroflowmetry DIAGNOSTIC_TEST

Uroflowmetry will be performed using a uroflow-cystometer (UroDoc Frytech) which determines Qmax, Qave and TQmax. Voided volume (in mL), voiding time (in sec), average and maximum urinary flow rate (Qave and Qmax in mL/sec), and time to maximum urinary flow (TQmax in sec) will be measured; urine flow acceleration (Qacc in mL/sec2) will be calculated. Qmax and Qave are defined according to the International Children's Continence Society. Voided volume will be measured by the uroflow-cystometer device; boys void in a standing, girls in a sitting position. Postvoid bladder diameter (mm) will be measured by ultrasonography and converted to bladder residual volume (mL). The device will be calibrated according to the prescribed instructions for use by a skilled technician. The examinations will take approximately 10 minutes.

Also known as: non-invasive urodynamic test

diabetic children; healthy children

Cardiovascular autonomic dysfunction test proposed by Ewing et al. DIAGNOSTIC_TEST

CAD will be assessed by five reproducible and standardized cardiovascular reflex tests described by Ewing et al. Three of the five tests assess parasympathetic function: heart rate response to deep breathing, to standing, and the Valsalva maneuver. Two tests evaluate sympathetic function which are blood pressure responses from lying to standing and at sustained handgrip. Each of these five tests is assigned a score of 0 for normal, 0.5 for borderline, and 1 for abnormal results. The sum of these 5 scores - which is the Ewing score - is used to assess severity of CAD. Patients having Ewing score ≥ 2 form the CAD + group, and patients who have less than 2 form the CAD - group.

diabetic children; healthy children

peripheral nerve conduction test DIAGNOSTIC_TEST

Peripheral neuropathy will be evaluated by nerve conduction test. The device measures motor conduction in the lower extremities. It operates at two dedicated frequencies in order to perform a thick myelin sheath cordless fibre (5Hz) and thin myelinated nerve fibre (2000Hz) examination. The device will be calibrated according to the prescribed instructions for use by a skilled technician.

diabetic children; healthy children

Eligibility Criteria

• Age: 5 Years - 18 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64)
• Sampling Method: Probability Sample

Study Population

Diabetic patients who are treated at the Endocrinology Department and Outpatient Clinic of Heim Pál National Pediatric Institute (HOGYI, Budapest, Hungary) will be enrolled.

You may qualify if:

• years (boys, girls) with type 1, type 2 and monogenic DM

You may not qualify if:

• Acute febrile condition (≥38 °C core temperature) in the past seven days
• Acute or chronical urinary tract or kidney disease: renal insufficiency (GFR ≤ 60 mL/min per 1.73 m2, urinary tract infection
• Urological disease: bladder cancer, urolithiasis, urethral stricture, posterior urethral valve, meatal stenosis, previous genitourinary surgery, conditions causing urinary outflow problems (phimosis, hypospadias, vesicoureteral reflux)
• Cystic fibrosis-related diabetes (CFRD)
• Neurological disorders (multiple sclerosis, transient ischaemic attack, transverse myelitis, myelocele, meningomyelocele, previous spinal cord operation, or operation which might injure the sacral nerve plexus)
• Medicines taken which can cause neuropathy:
• Cytostatic agents: cyclophosphamide, platinum-based antineoplastic agents, vinca alkaloids, epothilones, taxanes, proteasome inhibitors, immunomodulatory drugs
• Immunosuppressive agents: TNF-alfa inhibitors (adalimumab, infliximab, etanercept), interferon
• Cardiovascular medicines: statins, digoxin, amiodaron
• Antimicrobial agents: nitrofurantoin, linezolid, voriconazole, itraconazole, antituberculotics, metronidazole, fluoroquinolone
• Anti-ulcerative agent: cimetidin
• Neuropsychological agents: levodopa, fenitoin
• Psychiatric disorders that prevents participation / collaboration in the study
• Constipation (defined according to the Rome IV criteria)
• Voided volume \<20 mL

Sponsors & Collaborators

• Heim Pal Children's Hospital: lead

Study Sites (1)

Heim Pal National Pediatric Institute

Budapest, 1089, Hungary

Location

Related Publications (17)

• Petropoulos IN, Ponirakis G, Khan A, Almuhannadi H, Gad H, Malik RA. Diagnosing Diabetic Neuropathy: Something Old, Something New. Diabetes Metab J. 2018 Aug;42(4):255-269. doi: 10.4093/dmj.2018.0056.

  PMID: 30136449 BACKGROUND

• Yuan Z, Tang Z, He C, Tang W. Diabetic cystopathy: A review. J Diabetes. 2015 Jul;7(4):442-7. doi: 10.1111/1753-0407.12272. Epub 2015 Mar 24.

  PMID: 25619174 BACKGROUND

• Arrellano-Valdez F, Urrutia-Osorio M, Arroyo C, Soto-Vega E. A comprehensive review of urologic complications in patients with diabetes. Springerplus. 2014 Sep 23;3:549. doi: 10.1186/2193-1801-3-549. eCollection 2014.

  PMID: 25332855 BACKGROUND

• Fayyad AM, Hill SR, Jones G. Prevalence and risk factors for bothersome lower urinary tract symptoms in women with diabetes mellitus from hospital-based diabetes clinic. Int Urogynecol J Pelvic Floor Dysfunct. 2009 Nov;20(11):1339-44. doi: 10.1007/s00192-009-0949-z. Epub 2009 Jul 15.

  PMID: 19603127 BACKGROUND

• Kaplan SA, Te AE, Blaivas JG. Urodynamic findings in patients with diabetic cystopathy. J Urol. 1995 Feb;153(2):342-4. doi: 10.1097/00005392-199502000-00013.

  PMID: 7815578 BACKGROUND

• Agashe S, Petak S. Cardiac Autonomic Neuropathy in Diabetes Mellitus. Methodist Debakey Cardiovasc J. 2018 Oct-Dec;14(4):251-256. doi: 10.14797/mdcj-14-4-251.

  PMID: 30788010 BACKGROUND

• Ewing DJ, Clarke BF. Autonomic neuropathy: its diagnosis and prognosis. Clin Endocrinol Metab. 1986 Nov;15(4):855-88. doi: 10.1016/s0300-595x(86)80078-0.

  PMID: 3536203 BACKGROUND

• Barkai L, Szabo L. Urinary bladder dysfunction in diabetic children with and without subclinical cardiovascular autonomic neuropathy. Eur J Pediatr. 1993 Mar;152(3):190-2. doi: 10.1007/BF01956141.

  PMID: 8444242 BACKGROUND

• Szabo L, Barkai L, Lombay B. Urinary flow disturbance as an early sign of autonomic neuropathy in diabetic children and adolescents. Neurourol Urodyn. 2007;26(2):218-21. doi: 10.1002/nau.20349.

  PMID: 17078072 BACKGROUND

• Zajaczkowska R, Kocot-Kepska M, Leppert W, Wrzosek A, Mika J, Wordliczek J. Mechanisms of Chemotherapy-Induced Peripheral Neuropathy. Int J Mol Sci. 2019 Mar 22;20(6):1451. doi: 10.3390/ijms20061451.

  PMID: 30909387 BACKGROUND

• Jones MR, Urits I, Wolf J, Corrigan D, Colburn L, Peterson E, Williamson A, Viswanath O. Drug-Induced Peripheral Neuropathy: A Narrative Review. Curr Clin Pharmacol. 2020;15(1):38-48. doi: 10.2174/1574884714666190121154813.

  PMID: 30666914 BACKGROUND

• Ewing DJ, Martyn CN, Young RJ, Clarke BF. The value of cardiovascular autonomic function tests: 10 years experience in diabetes. Diabetes Care. 1985 Sep-Oct;8(5):491-8. doi: 10.2337/diacare.8.5.491.

  PMID: 4053936 BACKGROUND

• Spallone V, Bellavere F, Scionti L, Maule S, Quadri R, Bax G, Melga P, Viviani GL, Esposito K, Morganti R, Cortelli P; Diabetic Neuropathy Study Group of the Italian Society of Diabetology. Recommendations for the use of cardiovascular tests in diagnosing diabetic autonomic neuropathy. Nutr Metab Cardiovasc Dis. 2011 Jan;21(1):69-78. doi: 10.1016/j.numecd.2010.07.005.

  PMID: 21247746 BACKGROUND

• Lin K, Wei L, Huang Z, Zeng Q. Combination of Ewing test, heart rate variability, and heart rate turbulence analysis for early diagnosis of diabetic cardiac autonomic neuropathy. Medicine (Baltimore). 2017 Nov;96(45):e8296. doi: 10.1097/MD.0000000000008296.

  PMID: 29137013 BACKGROUND

• Liu G, Li M, Vasanji A, Daneshgari F. Temporal diabetes and diuresis-induced alteration of nerves and vasculature of the urinary bladder in the rat. BJU Int. 2011 Jun;107(12):1988-93. doi: 10.1111/j.1464-410X.2010.09840.x. Epub 2010 Nov 18.

  PMID: 21087392 BACKGROUND

• Beshay E, Carrier S. Oxidative stress plays a role in diabetes-induced bladder dysfunction in a rat model. Urology. 2004 Nov;64(5):1062-7. doi: 10.1016/j.urology.2004.06.021.

  PMID: 15533519 BACKGROUND

• Martonosi AR, Pazmany P, Kiss S, Zsakai A, Szabo L. INvesTigating the Abnormality of detrusor ConTractility by uroflowmetry in diabetic children (INTACT Trial): protocol of a prospective, observational study. BMJ Open. 2022 Nov 14;12(11):e062198. doi: 10.1136/bmjopen-2022-062198.

  PMID: 36375985 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Central Study Contacts

Szabó

CONTACT

0614599100; szabo.laszlo.md@gmail.com

Martonosi

CONTACT

agirmartonosi@gmail.com

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr. László Szabó M.D., PhD., DSc., Dr., Habil. pediatric nephrologist, urodynamic specialist

Study Record Dates

• First Submitted: January 18, 2022
• First Posted: February 21, 2022
• Study Start: September 1, 2022
• Primary Completion: September 1, 2023
• Study Completion (Estimated): September 1, 2027
• Last Updated: August 5, 2022

Record last verified: 2022-08

Locations

HU (1)